Summary Basis of Decision for Amitiza

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Amitiza is located below.

Recent Activity for Amitiza

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

The following  table describes post-authorization activity for Amitiza, a product which contains the medicinal ingredient lubiprostone. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

Updated: 2023-06-30

Drug Identification Number (DIN):

DIN 02447363 – 24 μg lubiprostone, capsule, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
DIN 02447363 cancelled (pre market) Not applicable Discontinuation date: 2020-12-17 The manufacturer notified Health Canada that sale of the drug has been discontinued pre market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
NDS # 179333 2014-10-31 Issued NOC 2015-10-14 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Amitiza

Date SBD issued: 2015-12-24

The following information relates to the new drug submission for Amitiza.

Lubiprostone, 24 µg, capsules, oral

Drug Identification Number (DIN):

  • 02447363

Sucampo Pharma Americas, LLC

New Drug Submission Control Number: 179333

 

On October 14, 2015, Health Canada issued a Notice of Compliance to Sucampo Pharma Americas, LLC for the drug product, Amitiza.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit/risk profile of Amitiza is favourable for the treatment of chronic idiopathic constipation (CIC) in adults.

  • The efficacy of Amitiza has been established in double-blinded, placebo-controlled clinical studies of four weeks duration. Efficacy of Amitiza beyond four weeks has not been established.
1 What was approved?

Amitiza, a selective ClC-2 chloride channel activator, was authorized for the treatment of chronic idiopathic constipation (CIC) in adults.

  • The efficacy of Amitiza has been established in double-blinded, placebo-controlled clinical studies of four weeks duration. Efficacy of Amitiza beyond four weeks has not been established.

No overall clinical differences in safety or efficacy have been observed between elderly and adult patients.

Amitiza is not recommended for use in children as the safety and efficacy of Amitiza in pediatric patients (<18 years of age) have not been established.

Amitiza is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. Amitiza is contraindicated in patients who are hypersensitive to the drug or any ingredient in the formulation. Amitiza was approved for use under the conditions stated in the Amitiza Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Amitiza (24 µg lubiprostone) is presented as capsules. In addition to the medicinal ingredient, the capsule contains medium-chain triglycerides, gelatin, sorbitol, black ink, and purified water. The black ink is composed of propylene glycol, black iron oxide, polyvinyl acetate phthalate, and polyethylene glycol. The product may contain trace levels of lecithin.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Amitiza Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Amitiza approved?

Health Canada considers that the benefit/risk profile of Amitiza is favourable for the treatment of chronic idiopathic constipation (CIC) in adults.

  • The efficacy of Amitiza has been established in double-blinded, placebo-controlled clinical studies of four weeks duration. Efficacy of Amitiza beyond four weeks has not been established.

Constipation is defined by infrequent or difficult passage of stool. The term chronic idiopathic constipation (CIC) refers to the long-term condition of constipation with an unknown causality. The symptoms of CIC [for example (e.g.), infrequent bowel movement, incomplete evacuation, abdominal bloating, straining at defecation, hard or lumpy stools] may be the result of inadequate colonic motility that can delay the transit of intestinal contents and impede the evacuation of rectal contents. The prevalence of CIC in the general population is estimated to be between 12% and 19%. Constipation is more likely to affect females than males, and is more likely to occur in older adults, showing a dramatic increase beyond 65 years of age. Despite the approval of various products for the treatment of constipation, not all products are efficacious in all patients, particularly given the different etiologies proposed for CIC, and the distinct mechanisms of action of these products. As a result, a need still exists for the availability of alternate prescription products for the treatment of CIC.

Amitiza was developed as a novel treatment for CIC; a product that stimulates the secretion of fluid into the abdominal lumen via the activation of chloride channels in the apical membrane of the epithelium and enhances stool passage.

Amitiza has been shown to be efficacious in adult patients with CIC. The market authorization was based on three pivotal double-blind, placebo-controlled studies of similar design. Patients treated with Amitiza had a greater proportion of patient responders that experienced a clinically relevant increase in stool frequency compared to patients treated with placebo. Pooled results of the three pivotal clinical studies showed a 17.1% difference in responders in favour of Amitiza. Additionally, Amitiza was associated with a greater proportion of patient responders that experienced a clinically relevant softening of stool and reduction in degree of straining compared to placebo. A pooled analysis of the pivotal studies resulted in a 21.3% and 14.3% difference in responders in favour of Amitiza with respect to stool consistency and degree of straining, respectively. Additional efficacy outcomes including weekly stool frequency, time to first stool, and event of rescue medication use, were all favourable towards Amitiza compared to placebo. These data, however, are limited to 4 weeks duration. The efficacy of Amitiza beyond 4 weeks has not been established.

Amitiza was generally well-tolerated, with the majority of reported adverse events (AEs) being mild to moderate in intensity. For patients treated with Amitiza in the placebo-controlled studies, the most commonly observed adverse reactions were consistent with the pharmacodynamics of the drug. These events included nausea (23.6%), diarrhea (8.3%), abdominal pain (6.3%), headache (8.0%), and dizziness (4.7%). Additional AEs of interest included chest discomfort/pain (2.3%), dyspnea (1.7%), and palpitations (1.0%). There was no evidence of a drug-drug interaction in the context of treatment of patients with CIC. There is no anticipated risk of abuse or misuse with Amitiza. This drug product has been marketed in the United States since 2006 for the indication of CIC with over 10 million prescriptions worldwide and over 1,000,000 subject-years of exposure. Post-market data gives reassurance as to a favourable benefit/risk profile of Amitiza in clinical practice.

The RMP for Amitiza was submitted by Sucampo Pharma Americas, LLC to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

Overall, the therapeutic benefits seen in the three pivotal studies are positive and the benefits of Amitiza therapy are considered to outweigh the potential risks. Amitiza has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, and can be adequately monitored clinically. Appropriate warnings and precautions are in place in the Amitiza Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Amitiza?

Submission Milestones: Amitiza

Submission Milestone Date
Pre-submission meeting: 2008-01-16 - 2014-02-27
Submission filed: 2014-10-31
Screening  
Screening Acceptance Letter issued: 2014-12-23
Review  
Biopharmaceutics Evaluation complete: 2015-09-17
Quality Evaluation complete: 2015-10-08
Clinical Evaluation complete: 2015-10-08
Labelling Review complete: 2015-10-08
Notice of Compliance issued by Director General: 2015-10-14

The Canadian regulatory decision on the non-clinical and clinical review of Amitiza was based on a critical assessment of the Canadian data package. The foreign review completed by the European Union's mutual recognition procedure with the United Kingdom as Reference Member State was used as an added reference for the clinical review.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

Clinical Pharmacology

Lubiprostone, the medicinal ingredient of Amitiza, is a locally‑acting, chloride channel activator that promotes the secretion of a chloride-rich intestinal fluid without altering electrolyte concentrations in the serum. Lubiprostone acts by specifically activating the type-2 chloride channel (C1C-2), a normal constituent of the apical cell membrane of human intestinal epithelial cells, in a protein kinase A-independent mechanism. By increasing intestinal fluid secretion, lubiprostone can facilitate passage of the stool and alleviate some symptoms associated with constipation.

The clinical pharmacological data support the use of Amitiza for the treatment of chronic idiopathic constipation (CIC) in adults.

Patients with hepatic impairment taking Amitiza may experience higher systemic drug exposure and higher frequency and severity of adverse reactions, therefore, Amitiza is not recommended in patients with severe hepatic impairment.

For further details, please refer to the Amitiza Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Amitiza (lubiprostone) for the treatment of chronic idiopathic constipation (CIC) was established in three pivotal, Phase III, double-blind, placebo‑controlled, randomized, multicentre clinical studies (SC0131, SC0232, and CC0831). In Studies SC0131 and SC0232 (both conducted in the United States), 81% of patients were White, 10% were Black, and 7% were Hispanic. All of the patients (100%) enrolled in Study CC0831 (conducted in Japan) were Asian. In all of the studies, the majority of patients previously used laxatives. Constipation was defined as, on average, less than three spontaneous bowel movements (SBMs) per week in the absence of rescue medication use [that is (i.e.), enema or suppository]. A total of 603 patients were randomized; 301 patients received Amitiza twice daily (48 µg/day) and 302 received placebo twice daily for 4 weeks. The primary endpoint of Studies SC0131 and SC0232 was the frequency of SBM at Week 1. In Study CC0831, the primary endpoint was the change from baseline in frequency of SBMs at Week 1.

All three studies demonstrated that patients treated with Amitiza had a higher frequency of SBMs and significantly increased post-treatment changes from baseline in frequency of SBMs during Week 1 as compared to placebo‑treated patients. In all studies, results similar to those in Week 1 were also observed at Weeks 2 to 4 of therapy.

The pivotal studies were conducted at a time prior to the development of guidelines regarding evaluation of treatments for chronic constipation. In an effort to address current regulatory recommendations, a post-hoc cumulative responder analysis based on weekly SBM frequencies for the duration of the study was conducted. This analysis consisted of the proportion of patients with at least 3 SBMs/week and an increase of at least 1 SBM/week compared to baseline. A responder was defined as fulfilling these criteria for at least 3 weeks of the 4-week duration of the studies. Similar post-hoc responder-based analyses were performed for assessed symptomology parameters. These analyses consisted of the proportion of patients with at least a 1 point unit change on ordinal scale improvement in symptom [for example (e.g.), stool consistency, degree of straining] from baseline. A responder was defined as fulfilling this criterion for 3 weeks of the 4-week duration of the studies.

Amitiza was associated with a greater proportion of patient responders who experienced a clinically relevant increase in stool frequency, compared to placebo. A pooled analysis of the three pivotal studies resulted in a 17.1% difference in responders in favour of Amitiza. Overall, there was a consistent trend towards a greater proportion of patient responders treated with Amitiza compared to placebo.

Patients treated with Amitiza had a greater proportion of patient responders who experienced a clinically relevant softening of stool and reduction in degree of straining, compared to patients treated with placebo. A pooled analysis of the three pivotal studies resulted in a 21.3% and 14.3% difference in responders in favour of Amitiza with respect to stool consistency and degree of straining, respectively. Amitiza did not provide a significant reduction in abdominal discomfort; abdominal pain was not assessed. The sensation of completeness of evacuation was not assessed in Studies SC0131 or SC0232. The Japanese pivotal Study CC0831 detected a statistically significant reduction in sensation of incomplete evacuation associated with Amitiza compared to placebo at only the first week of treatment.

In all of the three pivotal studies, Amitiza demonstrated an increased proportion of patients achieving SBMs within the first 24 hours after administration, when compared to placebo.

The results were consistent in subpopulation analyses for gender, race, and elderly patients.

Additional efficacy outcomes including weekly stool frequency, time to first stool, and event of rescue medication use, were all favourable towards Amitiza compared to placebo.

Overall, data from the three pivotal studies demonstrated that Amitiza is efficacious in the treatment of CIC, based on an increased frequency of SBMs and improvement in stool consistency and degree of straining during defecation. These data, however, are only established for up to 4 weeks. This limited duration is inconsistent with current regulatory guidelines for the evaluation of medicinal products for the treatment of chronic constipation [European Medicines Agency Guideline on the Evaluation of Medicinal Products for the Treatment of Chronic Constipation (25 June 2015)], which recommends the establishment of efficacy for at least 12 weeks. In the absence of longer duration efficacy data from suitable placebo-controlled clinical studies, the Product Monograph for Amitiza is labelled to inform healthcare professionals and patients that the efficacy of Amitiza beyond 4 weeks has not been established.

For more information, refer to the Amitiza Product Monograph, approved by Health Canada and available through the Drug Product Database.

Indication

The New Drug Submission for Amitiza was filed with the following indications:

  • Treatment of chronic idiopathic constipation (CIC) and associated signs and symptoms such as stool consistency, straining, constipation severity, abdominal discomfort, and abdominal bloating in adults.
  • Treatment of opioid-induced constipation (OIC) and associated signs and symptoms such as stool consistency, straining, constipation severity, abdominal discomfort, and abdominal bloating in adults with chronic, non-cancer pain.

Due to insufficient evidence of efficacy to support the use of Amitiza for OIC, Health Canada recommended the following indication:

  • Amitiza (lubiprostone) is indicated for the treatment of chronic idiopathic constipation (CIC) in adults.
    • The efficacy of Amitiza has been established in double-blinded, placebo-controlled clinical studies of 4 weeks duration. Efficacy of Amitiza beyond 4 weeks has not been established.

Based on the data submitted, the anticipated benefits of Amitiza are considered to outweigh the risks in patients with CIC only.

Clinical Safety

The clinical safety of Amitiza administered as 24 µg twice daily was evaluated in 301 patients with chronic idiopathic constipation (CIC) in three Phase III, double-blind, placebo-controlled clinical studies (SC0131, SC0232,and CC0831) described in the Clinical Efficacy section. In addition, 784 patients with CIC were treated in open-label studies with Amitiza for up to 12 months. Overall, 650 and 297 patients were treated with Amitiza for 6 months and 12 months, respectively, in clinical studies comprised of patients with CIC. Additionally, Amitiza has been marketed in the United States since 2006 for the indication of CIC with over 10 million prescriptions worldwide and over 1,000,000 subject years exposure as of 31 July 2015. This complementary clinical safety experience with Amitiza was captured in a Periodic Safety Update Report included in the submission.

Amitiza was generally well-tolerated, with a majority of reported adverse events (AEs) being mild to moderate in intensity. The most commonly observed adverse reactions in Amitiza‑treated CIC patients from the placebo-controlled studies were consistent with the pharmacodynamics of the drug. These events included nausea (23.6%), diarrhea (8.3%), abdominal pain (6.3%), headache (8.0%), and dizziness (4.7%). Additional common (≥1%) adverse reactions of interest that occurred less frequently than those previously mentioned include chest discomfort/pain (2.3%), dyspnea (1.7%), and palpitations (1.0%).

None of the patients treated with Amitiza experienced a serious AE in the placebo-controlled studies. Discontinuations due to AEs were 8.0% in the Amitiza group and 0.7% in the placebo group. The most common reason for study discontinuation was nausea.

In the open-label studies, the safety profile of Amitiza was relatively consistent with that of the placebo-controlled studies. The most common body system for adverse drug reactions included gastrointestinal disorders and nervous system disorders. Long-term treatment with Amitiza was most commonly associated with adverse reactions of nausea, diarrhea, abdominal discomfort/pain, and headache.

No patients died in the open-label studies. The most frequently reported severe AEs were nausea, abdominal distension, and diarrhea. Nausea was the most frequently reported treatment-related AE. The most frequently reported AEs resulting in treatment discontinuation were nausea, headache, dizziness, abdominal distention/pain, diarrhea, and vomiting. In these studies, approximately 20% of patients required a dose decrease; the majority of these dose decreases were due to AEs of diarrhea/loose stools, nausea, cramps, and excessive stool frequency. Adverse events of syncope, atrial fibrillation, palpitation, and chest discomfort/pain, although reported infrequently, have been observed with Amitiza.

Patients with hepatic impairment taking Amitiza may experience higher systemic drug exposure and higher frequency and severity of adverse reactions. Amitiza is not recommended in patients with severe hepatic impairment. A dosage adjustment is recommended for patients with moderate hepatic impairment.

Overall, Amitiza was generally well-tolerated, and appears to exhibit an acceptable safety profile in the treatment of patients for CIC. Appropriate warnings and precautions are in place in the approved Amitiza Product Monograph to address the identified safety concerns.

For more information, refer to the Amitiza Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The non-clinical development package for Amitiza (lubiprostone) was a comprehensive investigational program that included studies in vitro and in vivo pharmacodynamics, safety pharmacology, pharmacokinetics, toxicity, genotoxicity, carcinogenicity, antigenicity and reproductive and developmental toxicity. Based on these non-clinical studies, there are no major concerns that would predict unexpected adverse effects in patients treated with Amitiza at the recommended therapeutic dose.

Possible issues that may be of concern for human safety include:

  • Lubiprostone induced fetal loss in guinea pigs at dose levels that were 0.2 to 6 times of the proposed human dose (based on body surface). Such losses were observed under conditions of increased maternal toxicity and stress. It remains inconclusive from these data if the losses were a direct effect of lubiprostone or were related to the maternal toxicity and stress.
  • Neither lubiprostone nor its active metabolite were detectable in breast milk of rats; however, other inactive metabolites were observed to pass the placental barrier and also pass into breast milk. The potential pharmacodynamic and toxicological effect of these metabolites in neonates is unknown.
  • In monkeys, no lubiprostone-related fetal loss was seen at doses of 10 and 30 µg/kg/day (approximately 3 and 10 times the recommended human dose, respectively, based on body surface area) administered on Days 110 to 130 of gestation. Fetal loss was noted in one monkey from the 10 µg/kg/day dose group, which is within normal historical rates for this species.
  • Lubiprostone use is not recommended during pregnancy or in women of child bearing potential not using contraception. Caution should be exercised if lubiprostone is administered to nursing women.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Amitiza Product Monograph. Appropriate warnings and precautionary measures are in place in the Amitiza Product Monograph to address the identified safety concerns. Overall, the non-clinical studies support the use of Amitiza for the specified indication.

For more information, refer to the Amitiza Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Amitiza has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf‑life of 48 months is considered acceptable.

Proposed limits of drug-related impurities are considered adequately qualified [that is (i.e.) within International Council for Harmonisation (ICH) limits and/or qualified from toxicological studies].

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

Following investigations, Amitiza capsules were found to be compliant with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01, Revision 3). The gelatin used to manufacture the soft gelatin capsules for these formulations was also produced in compliance with the above note.

Certification letters attesting to these claims were provided by the sponsor.